Jiang Qingguang, Heneka Michael, Landreth Gary E
Department of Neurosciences, Alzheimer Research Laboratory, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA.
CNS Drugs. 2008;22(1):1-14. doi: 10.2165/00023210-200822010-00001.
Alzheimer's disease is a complex neurodegenerative disorder, with aging, genetic and environmental factors contributing to its development and progression. The complexity of Alzheimer's disease presents substantial challenges for the development of new therapeutic agents. Alzheimer's disease is typified by pathological depositions of beta-amyloid peptides and neurofibrillary tangles within the diseased brain. It has also been demonstrated to be associated with a significant microglia-mediated inflammatory component, dysregulated lipid homeostasis and regional deficits in glucose metabolism within the brain. The peroxisome proliferator-activated receptor-gamma (PPARgamma) is a prototypical ligand-activated nuclear receptor that coordinates lipid, glucose and energy metabolism, and is found in elevated levels in the brains of individuals with Alzheimer's disease. A recently appreciated physiological function of this type of receptor is its ability to modulate inflammatory responses. In animal models of Alzheimer's disease, PPARgamma agonist treatment results in the reduction of amyloid plaque burden, reduced inflammation and reversal of disease-related behavioural impairment. In a recent phase II clinical trial, the use of the PPARgamma agonist rosiglitazone was associated with improved cognition and memory in patients with mild to moderate Alzheimer's disease. Thus, PPARgamma may act to modulate multiple pathophysiological mechanisms that contribute to Alzheimer's disease, and represents an attractive therapeutic target for the treatment of the disease.
阿尔茨海默病是一种复杂的神经退行性疾病，衰老、遗传和环境因素都对其发生和发展有影响。阿尔茨海默病的复杂性给新型治疗药物的研发带来了巨大挑战。阿尔茨海默病的典型特征是患病大脑中β-淀粉样肽的病理性沉积和神经原纤维缠结。研究还表明，它与显著的小胶质细胞介导的炎症成分、脂质稳态失调以及大脑内葡萄糖代谢的区域缺陷有关。过氧化物酶体增殖物激活受体γ（PPARγ）是一种典型的配体激活核受体，可协调脂质、葡萄糖和能量代谢，在阿尔茨海默病患者大脑中的水平升高。这类受体最近被认识到的生理功能是其调节炎症反应的能力。在阿尔茨海默病动物模型中，PPARγ激动剂治疗可减轻淀粉样斑块负担、减轻炎症并逆转与疾病相关的行为障碍。在最近的一项II期临床试验中，使用PPARγ激动剂罗格列酮与轻度至中度阿尔茨海默病患者的认知和记忆改善有关。因此，PPARγ可能通过调节多种导致阿尔茨海默病的病理生理机制发挥作用，是治疗该疾病的一个有吸引力的治疗靶点。
